tbuckley/cabot-search huggingface dataset:
Restoring arm function with a soft robotic wearable for individuals with amyotrophic lateral sclerosis
Authors: Tommaso Proietti, Ciaran O’Neill, Lucas Gerez, Tazzy Cole, Sarah Mendelowitz, Kristin Nuckols, Cameron Hohimer, David Lin, Sabrina Paganoni, Conor Walsh
Journal: Science Translational Medicine (2023)

Despite promising results in the rehabilitation field, it remains unclear whether upper limb robotic wearables, e.g., for people with physical impairments resulting from neurodegenerative disease, can be made portable and suitable for everyday use. We present a lightweight, fully portable, textile-based, soft inflatable wearable robot for shoulder elevation assistance that provides dynamic active support to the upper limbs. The technology is mechanically transparent when unpowered, can quantitatively assess free movement of the user, and adds only 150 grams of weight to each upper limb. In 10 individuals with amyotrophic lateral sclerosis (ALS) with different degrees of neuromuscular impairment, we demonstrated immediate improvement in the active range of motion and compensation for continuing physical deterioration in two individuals with ALS over 6 months. Along with improvements in movement, we show that this robotic wearable can improve functional activity without any training, restoring performance of basic activities of daily living. In addition, a reduction in shoulder muscle activity and perceived muscular exertion, coupled with increased endurance for holding objects, highlight the potential of this device to mitigate the impact of muscular fatigue for patients with ALS. These results represent a further step toward everyday use of assistive, soft, robotic wearables for the upper limbs.
Epigenetic modification of <i>CSDE1</i> locus dictates immune recognition of nascent tumorigenic cells
Authors: Jiadi Lv, Yabo Zhou, Nannan Zhou, Zhenfeng Wang, Jie Chen, Haoran Chen, Dianheng Wang, Li Zhou, Keke Wei, Huafeng Zhang, Ke Tang, Jingwei Ma, Yuying Liu, Yonghong Wan, Yi Zhang, Haizeng Zhang, Bo Huang
Journal: Science Translational Medicine (2023)

Weak immunogenicity of tumor cells is a root cause for the ultimate failure of immunosurveillance and immunotherapy. Although tumor evolution can be shaped by immunoediting toward a less immunogenic phenotype, mechanisms governing the initial immunogenicity of primordial tumor cells or original cancer stem cells remain obscure. Here, using a single tumor-repopulating cell (TRC) to form tumors in immunodeficient or immunocompetent mice, we demonstrated that immunogenic heterogeneity is an inherent trait of tumorigenic cells defined by the activation status of signal transducer and activator of transcription 1 (STAT1) protein in the absence of immune pressure. Subsequent investigation identified that the RNA binding protein cold shock domain–containing protein E1 (CSDE1) can promote STAT1 dephosphorylation by stabilizing T cell protein tyrosine phosphatase (TCPTP). A methyltransferase SET and MYN domain–containing 3 (SMYD3) was further identified to mediate H3K4 trimethylation of CSDE1 locus, which was under the regulation of mechanotransduction by cell-matrix and cell-cell contacts. Thus, owing to the differential epigenetic modification and subsequent differential expression of CSDE1, nascent tumorigenic cells may exhibit either a high or low immunogenicity. This identified SMYD3-CSDE1 pathway represents a potential prognostic marker for cancer immunotherapy effectiveness that requires further investigation.
Budesonide/formoterol maintenance and reliever therapy versus fluticasone/salmeterol fixed-dose treatment in patients with COPD
Authors: Susan Muiser, Kai Imkamp, Dianne Seigers, Nynke J Halbersma, Judith M Vonk, Bart H D Luijk, Gert-Jan Braunstahl, Jan-Willem van den Berg, Bart-Jan Kroesen, Janwillem W H Kocks, Irene H Heijink, Helen K Reddel, Huib A M Kerstjens, Maarten van den Berge
Journal: Thorax (2023)

Background Maintenance and reliever therapy (MART) with inhaled corticosteroid (ICS)/formoterol effectively reduces exacerbations in asthma. We aimed to investigate its efficacy compared with fixed-dose fluticasone/salmeterol in chronic obstructive pulmonary disease (COPD). Methods Patients with COPD and ≥1 exacerbation in the previous 2 years were randomly assigned to open-label MART (Spiromax budesonide/formoterol 160/4.5 µg 2 inhalations twice daily+1 prn) or fixed-dose therapy (Diskus fluticasone propionate/salmeterol combination (FSC) 500/50 µg 1 inhalation twice daily+salbutamol 100 µg prn) for 1 year. The primary outcome was rate of moderate/severe exacerbations, defined by treatment with oral prednisolone and/or antibiotics. Results In total, 195 patients were randomised (MART Bud/Form n=103; fixed-dose FSC n=92). No significant difference was seen between MART and FSC therapy in exacerbation rates (1.32 vs 1.32 /year, respectively, rate ratio 1.05 (95% CI 0.79 to 1.39); p=0.741). No differences in lung function parameters or health status were observed. Total ICS dose was significantly lower with MART than FSC therapy (budesonide-equivalent 928 µg/day vs 1747 µg/day, respectively, p&lt;0.05). Similar proportions of patients reported adverse events (MART Bud/Form: 73% vs fixed-dose FSC: 68%, p=0.408) and pneumonias (MART: 5% vs FSC: 1%, p=0.216). Conclusions This first study of MART in COPD found that budesonide/formoterol MART might be similarly effective to fluticasone/salmeterol fixed-dose therapy in moderate to severe patients with COPD, at a lower daily ICS dosage. Further evidence is needed about long-term safety.
Are we levelling the playing field? A qualitative case study of the awareness, uptake and relevance of the IOC consensus statements in two countries
Authors: Lauren V Fortington, Marelise Badenhorst, Caroline Bolling, Wayne Derman, Carolyn A Emery, Kati Pasanen, Martin Schwellnus, Evert Verhagen, Caroline F Finch AO
Journal: British Journal of Sports Medicine (2023)

Research evidence is commonly compiled into expert-informed consensus guidelines intended to consolidate and distribute sports medicine knowledge. Between 2003 and 2018, 27 International Olympic Committee (IOC) consensus statements were produced. This study explored the policy and practice impact of the IOC Statements on athlete health and medical team management in two economically and contextually diverse countries.A qualitative case study design was adopted. Fourteen face-to-face interviews were conducted with purposively selected interviewees, seven participants from Australia (higher economic equality) and seven from South Africa (lower economic equality), representing their national medical commissions (doctors and physiotherapists of Olympic, Paralympic and Youth teams). A framework method was used to analyse interview transcripts and identify key themes.Differences across resource settings were found, particularly in the perceived usefulness of the IOC Statements and their accessibility. Both settings were unsure about the purpose of the IOC Statements and their intended audience. However, both valued the existence of evidence-informed guidelines. In the Australian setting, there was less reliance on the resources developed by the IOC, preferring to use locally contextualised documents that are readily available.The IOC Statements are valuable evidence-informed resources that support translation of knowledge into clinical sports medicine practice. However, to be fully effective, they must be perceived as useful and relevant and should reach their target audiences with ready access. This study showed different contexts require different resources, levels of support and dissemination approaches. Future development and dissemination of IOC Statements should consider the perspectives and the diversity of contexts they are intended for.
In silico method to maximise the biological potential of understudied metabolomic biomarkers: a study in pre-eclampsia
Authors: Huimin Zheng, Feihong Mai, Siyou Zhang, Zixin Lan, Zhang Wang, Shanwei Lan, Renfang Zhang, Dong Liang, Guoqiang Chen, Xia Chen, Yinglin Feng
Journal: Gut (2023)
Anti-brolucizumab immune response as one prerequisite for rare retinal vasculitis/retinal vascular occlusion adverse events
Authors: Anette C. Karle, Matthias B. Wrobel, Stephan Koepke, Michael Gutknecht, Sascha Gottlieb, Brigitte Christen, Tina Rubic-Schneider, Ingrid Pruimboom-Brees, Xavier Charles Leber, Meike Scharenberg, Benjamin Maciejewski, Oliver Turner, Chandra Saravanan, Francois Huet, Amanda Littlewood-Evans, Andreas Clemens, Cynthia L. Grosskreutz, Jeffrey D. Kearns, Pawan Mehan, Robert L. Schmouder, Vito Sasseville, Dominique Brees
Journal: Science Translational Medicine (2023)

In October 2019, Novartis launched brolucizumab, a single-chain variable fragment molecule targeting vascular endothelial growth factor A, for the treatment of neovascular age-related macular degeneration. In 2020, rare cases of retinal vasculitis and/or retinal vascular occlusion (RV/RO) were reported, often during the first few months after treatment initiation, consistent with a possible immunologic pathobiology. This finding was inconsistent with preclinical studies in cynomolgus monkeys that demonstrated no drug-related intraocular inflammation, or RV/RO, despite the presence of preexisting and treatment-emergent antidrug antibodies (ADAs) in some animals. In this study, the immune response against brolucizumab in humans was assessed using samples from clinical trials and clinical practice. In the brolucizumab-naïve population, anti-brolucizumab ADA responses were detected before any treatment, which was supported by the finding that healthy donors can harbor brolucizumab-specific B cells. This suggested prior exposure of the immune system to proteins with structural similarity. Experiments on samples showed that naïve and brolucizumab-treated ADA-positive patients developed a class-switched, high-affinity immune response, with several linear epitopes being recognized by ADAs. Only patients with RV/RO showed a meaningful T cell response upon recall with brolucizumab. Further studies in cynomolgus monkeys preimmunized against brolucizumab with adjuvant followed by intravitreal brolucizumab challenge demonstrated that high ADA titers were required to generate ocular inflammation and vasculitis/vascular thrombosis, comparable to RV/RO in humans. Immunogenicity therefore seems to be a prerequisite to develop RV/RO. However, because only 2.1% of patients with ADA develop RV/RO, additional factors must play a role in the development of RV/RO.
A Novel Three-dimensional Planning Tool for Selective Clamping During Partial Nephrectomy: Validation of a Perfusion Zone Algorithm
Authors: Pieter De Backer, Saar Vermijs, Charles Van Praet, Pieter De Visschere, Sarah Vandenbulcke, Angelo Mottaran, Carlo A. Bravi, Camille Berquin, Edward Lambert, Stéphanie Dautricourt, Wouter Goedertier, Alexandre Mottrie, Charlotte Debbaut, Karel Decaestecker
Journal: European Urology (2023)
Circulating Tumor DNA Is Prognostic in Intermediate-Risk Rhabdomyosarcoma: A Report From the Children's Oncology Group
Authors: Samuel Abbou, Kelly Klega, Junko Tsuji, Mohammad Tanhaemami, David Hall, Donald A. Barkauskas, Mark D. Krailo, Carrie Cibulskis, Anwesha Nag, Aaron R. Thorner, Samuel Pollock, Alma Imamovic-Tuco, Jack F. Shern, Steven G. DuBois, Rajkumar Venkatramani, Douglas S. Hawkins, Brian D. Crompton
Journal: Journal of Clinical Oncology (2023)

Novel biomarkers are needed to differentiate outcomes in intermediate-risk rhabdomyosarcoma (IR RMS). We sought to evaluate strategies for identifying circulating tumor DNA (ctDNA) in IR RMS and to determine whether ctDNA detection before therapy is associated with outcome.
A root cause analysis to identify the mechanistic drivers of immunogenicity against the anti-VEGF biotherapeutic brolucizumab
Authors: Jeffrey D. Kearns, Paul Wassmann, Ufuk Olgac, Marie Fichter, Brigitte Christen, Tina Rubic-Schneider, Stephan Koepke, Benjamin Cochin de Billy, David Ledieu, Cedric Andre, Stuart Hawtin, Benoit Fischer, Francesca Moretti, Christian Hug, Alexander Bepperling, Barbara Brannetti, Celia Mendez-Garcia, Amanda Littlewood-Evans, Andreas Clemens, Cynthia L. Grosskreutz, Pawan Mehan, Robert L. Schmouder, Vito Sasseville, Dominique Brees, Anette C. Karle
Journal: Science Translational Medicine (2023)

Immunogenicity against intravitreally administered brolucizumab has been previously described and associated with cases of severe intraocular inflammation, including retinal vasculitis/retinal vascular occlusion (RV/RO). The presence of antidrug antibodies (ADAs) in these patients led to the initial hypothesis that immune complexes could be key mediators. Although the formation of ADAs and immune complexes may be a prerequisite, other factors likely contribute to some patients having RV/RO, whereas the vast majority do not. To identify and characterize the mechanistic drivers underlying the immunogenicity of brolucizumab and the consequence of subsequent ADA-induced immune complex formation, a translational approach was performed to bridge physicochemical characterization, structural modeling, sequence analysis, immunological assays, and a quantitative systems pharmacology model that mimics physiological conditions within the eye. This approach revealed that multiple factors contributed to the increased immunogenic potential of brolucizumab, including a linear epitope shared with bacteria, non-natural surfaces due to the single-chain variable fragment format, and non-native drug species that may form over prolonged time in the eye. Consideration of intraocular drug pharmacology and disease state in a quantitative systems pharmacology model suggested that immune complexes could form at immunologically relevant concentrations modulated by dose intensity. Assays using circulating immune cells from treated patients or treatment-naïve healthy volunteers revealed the capacity of immune complexes to trigger cellular responses such as enhanced antigen presentation, platelet aggregation, endothelial cell activation, and cytokine release. Together, these studies informed a mechanistic understanding of the clinically observed immunogenicity of brolucizumab and associated cases of RV/RO.
Cyb5r3-based mechanism and reversal of secondary failure to sulfonylurea in diabetes
Authors: Hitoshi Watanabe, Wen Du, Jinsook Son, Lina Sui, Shun-ichiro Asahara, Irwin J. Kurland, Taiyi Kuo, Takumi Kitamoto, Yasutaka Miyachi, Rafael de Cabo, Domenico Accili
Journal: Science Translational Medicine (2023)

Sulfonylureas (SUs) are effective and affordable antidiabetic drugs. However, chronic use leads to secondary failure, limiting their utilization. Here, we identify cytochrome b5 reductase 3 (Cyb5r3) down-regulation as a mechanism of secondary SU failure and successfully reverse it. Chronic exposure to SU lowered Cyb5r3 abundance and reduced islet glucose utilization in mice in vivo and in ex vivo murine islets. Cyb5r3 β cell–specific knockout mice phenocopied SU failure. Cyb5r3 engaged in a glucose-dependent interaction that stabilizes glucokinase (Gck) to maintain glucose utilization. Hence, Gck activators can circumvent Cyb5r3-dependent SU failure. A Cyb5r3 activator rescued secondary SU failure in mice in vivo and restored insulin secretion in ex vivo human islets. We conclude that Cyb5r3 is a key factor in the secondary failure to SU and a potential target for its prevention, which might rehabilitate SU use in diabetes.
Good Radiosensitizer Hunting
Authors: Loren K. Mell, Stuart J. Wong
Journal: Journal of Clinical Oncology (2023)

2][3][4][5][6][7] However, cisplatin may be poorly tolerated or contraindicated in patients with renal insufficiency, neuropathy, hearing loss, poor performance status, advanced age, and/or multiple comorbidities, 8 a group comprising up to one third of the overall HNSCC population. 9,10With advancing age of the global population, the number of patients with HNSCC receiving alternatives to cisplatin continues to rise. 11
Characterising airway obstructive, dysanaptic and PRISm phenotypes of prematurity-associated lung disease
Authors: Michael Cousins, Kylie Hart, Sarah J Kotecha, A John Henderson, W John Watkins, Andrew Bush, Sailesh Kotecha
Journal: Thorax (2023)

Introduction Although obstructive airway disease has been shown to be associated with prematurity, other spirometry phenotypes are less well described. Objectives We characterised abnormal spirometry phenotypes in preterm-born children, including prematurity-associated obstructive lung disease (POLD, forced expiratory volume in 1 s (FEV 1 )&lt;lower limit of normal (LLN), FEV 1 /forced vital capacity (FVC)&lt;LLN), prematurity-associated preserved ratio of impaired spirometry (pPRISm, FEV 1 &lt;LLN, FEV 1 /FVC≥LLN) and prematurity-associated dysanapsis (pDysanapsis, FEV 1 ≥LLN, FEV 1 /FVC&lt;LLN), and associated them with early life factors, bronchodilator responsiveness and fractional exhaled nitric oxide (FE NO ). Methods 768 children, aged 7–12 years, underwent FE NO measurements and spirometry before and after salbutamol. Groups were compared using parametric tests; multinomial regression was used. Results 22.6% of 544 preterm-born (mean gestation: 31 weeks) and 9.2% of 195 term-born children, with satisfactory data available, were classified into one of four abnormal spirometry groups. Each phenotype was generally more prevalent in preterm-born children than in the term-born children. For the preterm group, POLD-reversible (4.4%) was associated with increased FE NO , bronchopulmonary dysplasia (BPD) and intrauterine growth restriction. POLD-fixed group (3.3%) did not have increased FE NO but was associated with BPD. 41% of the pDysanapsis group (5.9%) had bronchodilator response, 31% had increased FE NO and was associated with postnatal weight gain. In the pPRISm group (9%), 13% responded to bronchodilators, FE NO was not increased and was non-significantly associated with body mass index (p=0.064). Conclusions Further to airway obstruction, we describe airway dysanapsis and pPRISm spirometry phenotypes in survivors of prematurity, both of which have poor outlook in other disease groups. By identifying specific phenotypes, targeted therapy can be developed to improve long-term outcomes.
Polydopamine-coated i-motif DNA/Gold nanoplatforms for synergistic photothermal-chemotherapy
Authors: Bo Chen, Lan Mei, Rangrang Fan, Di Chuan, Yangmei Ren, Min Mu, Haifeng Chen, Bingwen Zou, Gang Guo
Journal: Asian Journal of Pharmaceutical Sciences (2023)

The combination of photothermal therapy with chemotherapy has gradually developed into promising cancer therapy. Here, a synergistic photothermal-chemotherapy nanoplatform based on polydopamine (PDA)-coated gold nanoparticles (AuNPs) were facilely achieved via the in situ polymerization of dopamine (DA) on the surface of AuNPs. This nanoplatform exhibited augmented photothermal conversion efficiency and enhanced colloidal stability in comparison with uncoated PDA shell AuNPs. The i-motif DNA nanostructure was assembled on PDA-coated AuNPs, which could be transformed into a C-quadruplex structure under an acidic environment, showing a characteristic pH response. The PDA shell served as a linker between the AuNPs and the i-motif DNA nanostructure. To enhance the specific cellular uptake, the AS1411 aptamer was introduced to the DNA nanostructure employed as a targeting ligand. In addition, Dox-loaded NPs (DAu@PDA-AS141) showed the pH/photothermal-responsive release of Dox. The photothermal effect of DAu@PDA-AS141 elicited excellent photothermal performance and efficient cancer cell inhibition under 808 nm near-infrared (NIR) irradiation. Overall, these results demonstrate that the DAu@PDA-AS141 nanoplatform shows great potential in synergistic photothermal-chemotherapy.
Pan-cancer molecular subtypes of metastasis reveal distinct and evolving transcriptional programs
Authors: Yiqun Zhang, Fengju Chen, Chad J. Creighton
Journal: Cell Reports Medicine (2023)

Molecular mechanisms underlying cancer metastasis span diverse tissues of origin. Here, we synthesize and collate the transcriptomes of patient-derived xenografts and patient tumor metastases, and these data collectively represent 38 studies and over 3,000 patients and 4,000 tumors. We identify four expression-based subtypes of metastasis transcending tumor lineage. The first subtype has extensive copy alterations, higher expression of MYC transcriptional targets and DNA repair genes, and bromodomain inhibitor response association. The second subtype has higher expression of genes involving metabolism and prostaglandin synthesis and regulation. The third subtype has evidence of neuronal differentiation, higher expression of DNA and histone methylation genes and EZH2 transcriptional targets, and BCL2 inhibitor response association. The fourth subtype has higher expression of immune checkpoint and Notch pathway genes. The metastasis subtypes reflect expression differences from paired primaries, with subtype switching being common. These subtypes facilitate understanding of the molecular underpinnings of metastases beyond tissue-oriented domains, with therapeutic implications.
Agency affects pain inference through prior shift as opposed to likelihood precision modulation in a Bayesian pain model
Authors: Andreas Strube, Björn Horing, Michael Rose, Christian Büchel
Journal: Neuron (2023)

Agency and expectations play a crucial role in pain perception and treatment. In the Bayesian pain model, somatosensation (likelihood) and expectations (prior) are weighted by their precision and integrated to form a pain percept (posterior). Combining pain treatment with stimulus-related expectations allows the mechanistic assessment of whether agency enters this model as a shift of the prior or a relaxation of the likelihood precision. In two experiments, heat pain was sham treated either externally or by the subject, while a predictive cue was utilized to create high or low treatment expectations. Both experiments revealed additive effects and greater pain relief under self-treatment and high treatment expectations. Formal model comparisons favored a prior shift rather than a modulation of likelihood precision. Electroencephalography revealed a theta-to-alpha effect, temporally associated with expectations, which was correlated with trial-by-trial pain ratings, further supporting a prior shift through which agency exerts its influence in the Bayesian pain model.